Decitabine is currently being developed as a pharmaceutical for the treatment of chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), non-small cell lung (NSCL) cancer, sickle-cell anaemia, and acute myelogenous leukemia (AML). Decitabine possesses multiple pharmacological characteristics. Decitabine can be incorporated into DNA during the S phase of cell cycle, or can induce cell differentiation and exert haematological toxicity. Despite having a short physiological half-life, decitabine has an excellent tissue distribution.
Despite its proven antileukemic effects in CML, MDS, and AML, the potential application of decitabine has been hampered by delayed and prolonged myelosuppression. Lower doses of decitabine, given over a longer period of time, have minimized myelosuppression to manageable levels without compromising its ability to suppress cancer via its hypomethylation effect. At higher doses, the associated toxicity was prohibitive. However, treatment of haematologic and solid tumours at maximally tolerated doses of decitabine has been ineffective. The cause of myelosuppression is not clear. It is plausible that since decitabine is randomly and extensively incorporated into the DNA of S phase cells, including bone marrow cells that are involved in normal haematopoiesis, the severe DNA damage due to the instability of decitabine leads to necrosis. Since incorporation of decitabine is not restricted to only the CpG-rich sequences, the DNA can break, due to the instability of decitabine, and require repair at numerous sites outside of the CpG islands.
Decitabine and azacitidine are unstable in aqueous media and undergo hydrolytic degradation in aqueous media. The degradation is slowest at neutral pH.
Dinucleotide compounds derived from decitabine for the development of therapies for similar indications had been described in U.S. Pat. No. 7,700,567, which is incorporated by reference in its entirety.